Current Medicinal Chemistry - Volume 14, Issue 21, 2007

The human kinome describes a major group of intracellular signalling molecules. In the last few years, many molecules in the group have become targets for therapeutic interventions. Due to the conserved reaction mechanism of catalysis, protein kinases seem well “drugable” by small molecular weight inhibitors, thus opening the chance to novel oral bioavailable drug development. A large number of small molecule weight inhibitors for protein kinases have already been introduced into research and these molecules are extensively analysed in regard to their efficiency, potency and selectivity. Here we summarise the use of small molecule protein kinase inhibitors relevant for acute and chronic inflammation based on their essential role in cellular signaling mechanisms in immune cells such as macrophages, lymphoytes and granulocytes. We describe the progress made to develop inhibitors against Toll-like receptor associated kinases (IRAKs), against the MAPK kinase kinases Cot/Tpl-2 and TAK1, against Inhibitor-κB kinases (IKKs), against MAPK kinases (MEKs, MKKs), against MAPKs (ERK2, p38, JNKs) and against their downstream kinases MNK1 and MK2/3. This overview should help to keep up with the fast developing field and the continuously growing number of protein kinase inhibitors.

Allergic diseases constitute a major health issue worldwide. Mainstay treatment constitutes allergen avoidance and pharmacotherapy for symptom relief, but allergen immunotherapy offers advantages of specific treatment with long lasting efficacy, and being able to modify the course of the disease. Conventional immunotherapy involves the subcutaneous injection of gradually increasing amounts of allergen extract but the use of current whole allergen extracts is restricted by the risk of adverse IgE-mediated events especially for potent allergens such as peanut and latex and for asthmatics. This has lead to interest in alternative routes of immunotherapy. Oral tolerance is a well-documented immune process and the sublingual route of administration of allergen immunotherapy is attracting interest. Recent meta-analyses show that sublingual allergen immunotherapy for grass pollen and house dust mite allergy is clinically effective and safer than injection immunotherapy. Some studies show SLIT induces changes of T cell anergy, immune deviation, blocking antibodies, and induction of regulatory T cells, as described for injection immunotherapy pointing to the need to target allergen-specific T cells, there is emergent evidence that the oral mucosa presents distinct regulatory features. Evidence suggests that oral dendritic cells play a key role in inducing tolerance especially when allergen is taken up via Fc receptor bound IgE. This suggests that although both would target allergen-specific T cells, allergen formulations may differ with respect to IgE epitopes for optimal SLIT compared with SCIT. Identification of the molecular nature of the allergen-DC receptor interaction is required to determine whether short peptides or recombinant allergen preparations and of suitable adjuvants specifically tailored for the sublingual route will allow the development of improved allergen formulations and delivery strategies for efficacy of treatment whilst decreasing IgE-mediated adverse effects.

Three major mucosal systems exist in the body, the oral-gastrointestinal, the respiratory and the genitourinary systems. In particular, the gastrointestinal (GI) tract contains the largest mucosal surface in the body and is the major port of entry for foreign antigens. Therefore, the gut immune system has to differentiate to tolerate dietary antigens and expel infectious and harmful pathogens. During the complex but well-orchestrated immune responses in the mucosal system, T cells play a pivotal role in both immunity and tolerance. Of many T cell subpopulations, CD4+CD25+ T regulatory cells (Tregs) are instrumental in regulation of immune responses in mucosea. Among the multitude of cytokines and factors that are produced in the gut, Transforming Growth Factor-beta (TGF-β) is probably the most important one in influencing mucosal T cell responses. The interaction and mutual regulation between TGF-β and CD4+CD25+ Tregs may be the key in maintaining the balance between T cell immunity and tolerance in mucosal system. In this article, we attempt to discuss both beneficial and detrimental effects of TGF-β and Tregs on oral tolerance, mucosal inflammation and autoimmunity, colon cancer and HIV infection in the gut.

Asthma and chronic obstructive pulmonary disease (COPD) are two different inflammatory disorders of the lungs which share a common functional abnormality, i.e. airflow limitation [1,2]. In asthma, airflow limitation is largely reversible, either spontaneously or with treatment, and does not progress in most cases [1]. On the other hand, airflow limitation in COPD is usually progressive and poorly reversible [2]. In asthma, the chronic inflammation causes an associated increase in airway responsiveness to a variety of stimuli, leading to recurrent episodes of wheezing, breathlessness, chest tightness and cough, particularly at night and in the early morning. Many cells are involved in the inflammatory response in asthma and, among these, CD4+ Type-2 lymphocytes, mast cells and eosinophils are thought to play a crucial role. In COPD, the poorly reversible airflow limitation is associated with an abnormal inflammatory response of the lungs to noxious particles or gases [2]. This chronic inflammation is characterized by an increased number of CD8+ Type-1 T-lymphocytes and macrophages in the lung tissue and neutrophils in the airway lumen. Lymphocytes, which are markedly different in the two inflammatory conditions, play a crucial role in the pathogenesis of asthma and COPD. In this review, we will discuss the current concepts on the recruitment, homing and activity of lymphocytes in these two respiratory diseases.

Chemokine receptors are a target of growing interest for new therapeutic drugs, as their role in multiple disease states has been demonstrated. The CXCR4/ CXCL12 pairing has been implicated in HIV and cancer, as well as chronic inflammatory diseases, including asthma and rheumatoid arthritis. HIV uses CXCR4 or CCR5 receptors in the key binding step of the infection process, leading to the idea that drugs could be developed to block this interaction. Cancer metastasis has also been linked to cellular communication via the chemokine pathways and hence, receptor antagonists could potentially inhibit this important pathway of disease progression. A wealth of data concerning small molecule CXCR4 receptor antagonists has been generated over the last few years, as a variety of these small molecules have been tested, and the understanding of structure activity relationships has improved. Here, we review the developing area of small molecule CXCR4 antagonists and the rapidly increasing amount of data from biological studies. Both peptidic and non-peptidic compounds have been investigated. In particular, we focus on AMD3100 and bismacrocyclic analogues, the most extensively studied class of CXCR4 antagonists, and the recent developments in this area.

Erythropoietin (EPO) is a 30,400 daltons glycoprotein, consisting of 165 amino acids produced mainly in the kidney and in the liver and regulating erythrocyitosis. It primarily acts on erythroid precursor cell at colony-forming units-erythroid stage inhibiting the apoptosis. EPO binds on a specific membrane receptor thereby activating at least three specific intracellular signaling pathways, such as phosphatidylinositol 3-kinase/ protein kinase B, Ras-mitogen-activated protein kinase and some members of the signal transducers and activators of transcription family. In addition to kidney and liver, EPO mRNA has been detected in other tissues; accordingly EPO receptor has been identified in several type of cells and recent reports have suggested new roles for EPO in non-haematopoietic tissues with a robust evidence for neuroprotective and cardioprotective activity. In different animal models, in vitro, in isolated perfused heart and in vivo, recombinant human erythropoietin protects heart from ischemia reperfusion injury and reduces myocardial damage. EPO tissue protective activity can be separated from erythropoietic activity. Molecules owing the first property but not the second one have been described. In patients with acute myocardial infarction serum EPO level correlates inversely with infarct size. Acute coronary syndrome, extracorporeal circulation and percutaneous coronary intervention are potential fields of application for tissue protective EPO activity to reduce myocardial damage, increase cardiac function ad improve outcome.

Gap junctions, intercellular channels structured by the connexin protein family, have been implicated in the control of cell homeostasis, proliferation, differentiation and death. A loss of the gap junction intercellular communication and/or connexin dysfunction are typical features of cancer per se and have been associated with the effect of many carcinogens. Indeed, many early human neoplasia of various organs and human tumor cell lines exhibit deficient connexin-mediated communication expression mainly related, in a large number of observations, with an aberrant cytoplasmic localization of this membranous protein. Restoration of normal phenotype in transformed cells by restoration of exogenous connexin gave rise to the concept that connexins may act as tumor suppressors. However, the mechanisms by which connexins mediate such a tumor suppressor effect are multiple. They may result from: formation of functional channels; hemichannels or are directly associated with connexin expression. In addition, the literature shows that they may be dependent upon the cell type and the connexin type. In the present review, we analyze all these aspects of connexin/gap junction involvement in the carcinogenesis process, in human cancers and discuss the possibility of using connexins as potential anti-oncogenic targets for cancer chemoprevention and/or chemotherapy.

Sialic acid-containing oligosaccharides expressed on the respiratory tract epithelial cell surface are involved in influenza virus infection in both virus attaching and detaching processes. Therefore, inhibition of sialic acid-binding processes provides rational anti-influenza strategies. Previous exploring efforts using monosaccharide sialic acid-bearing macromolecules provided proof of concept for multivalent hemagglutinin inhibition. However, the monosaccharide sialic acid cannot account for the molecular determinant of virus receptor-binding specificity in the context of the whole sialyloligosaccharide receptor. On the other hand, neuraminidase inhibition efforts using sialylmimetics have resulted into two antiinfluenza drugs, zanamivir and oseltamivir, which have been shown to reduce both the severity and duration of influenza illness. Nevertheless, the usage of monomeric sialylmimetics requires relatively large amounts of expensive compounds, which may also induce virus resistance and side effect. Therefore, it is critical to develop new antiinfluenza drugs and improve the current antiinfluenza drugs. This review highlights recent explorations of multivalent sialyloligosaccharides-based influenza virus adhesion inhibition strategy and multivalent sialylmimetics-based influenza virus detachment inhibition strategy for these efforts.

Critically ill patients are at high risk for developing acute renal failure (ARF). The prevention of ARF is of outmost importance in order to improve the increased morbidity and mortality associated with ARF. Unfortunately, there is lack of adequate endogenous markers that can identify renal dysfunction early - this hampers timely application of measures to prevent further renal damage. The use of exogenous markers of renal function is not only time-consuming but also expensive, and therefore can not be used on a regular basis in the intensive care unit. Both the presently used endogenous and exogenous markers are not reliable during continuous renal replacement therapy (CRRT) because these markers are removed by the therapy itself impeding early detection of recovering of renal function. Cystatin C has been proposed as an alternative endogenous marker of renal function for more than 15 years. In this manuscript we review the literature on the role of cystatin C as marker for renal function, focusing on the critically ill patient. Serum cystatin C concentrations have been found to relate to renal impairment and suggest that cystatin C is more sensitive to detect mild decreases in GFR. Cystatin C could be an important tool both to recognize early renal dysfunction and to identify renal recovery while on CRRT in the critically ill patient, however, we are in need of more studies.